Constitutive ret activity in knock-in multiple endocrine neoplasia type B mice induces profound elevation of brain dopamine concentration via enhanced synthesis and increases the number of TH-positive cells in the substantia nigra

Jelena Mijatovic, Mikko Airavaara, Anu Planken, Petri Auvinen, Atso Raasmaja, Petteri Piepponen, Frank Costantini, Liisa Ahtee, Mart Saarma

    Research output: Contribution to journalArticleScientificpeer-review

    Abstract

    Ret is the common signaling receptor for glial cell line-derived neurotrophic factor (GDNF) and other ligands of the GDNF family that have potent effects on brain dopaminergic neurons. The Met918Thr mutation leads to constitutive activity of Ret receptor tyrosine kinase, causing the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). We used knock-in MEN2B mice with the Ret-MEN2B mutation to study the effects of constitutive Ret activity on the brain dopaminergic system and found robustly increased concentrations of dopamine (DA) and its metabolites in the striatum, cortex, and hypothalamus. The concentrations of brain serotonin were not affected and those of noradrenaline were slightly increased only in the lower brainstem. Tyrosine hydroxylase (TH) protein levels were increased in the striatum and substantia nigra/ventral tegmental area (SN/VTA), and TH mRNA levels were increased in SN/VTA of MEN2B mice, suggesting that constitutive Ret activity increases DA levels by increasing its synthesis. Also, the striatal DA transporter protein levels in the MEN2B mice were increased, which agrees with increased sensitivity of these mice to the stimulatory effects of cocaine. In the SN pars compacta of homozygous MEN2B mice, we found a 26% increase in the number of TH-positive cells, but no differences were found in the VTA. Thus, we show here that the constitutive Ret activity in mice is sufficient to increase the number of dopaminergic neurons and leads to profound elevation of brain DA concentration. These data clearly suggest that Ret activity per se can have a direct biological function that actively changes and shapes the brain dopaminergic system.
    Original languageEnglish
    JournalJournal of Neuroscience
    Volume27
    Issue number18
    Pages (from-to)4799-4809
    Number of pages11
    ISSN0270-6474
    DOIs
    Publication statusPublished - 2007
    MoE publication typeA1 Journal article-refereed

    Cite this

    @article{a950bd9d7a60484e936953c9211e549d,
    title = "Constitutive ret activity in knock-in multiple endocrine neoplasia type B mice induces profound elevation of brain dopamine concentration via enhanced synthesis and increases the number of TH-positive cells in the substantia nigra",
    abstract = "Ret is the common signaling receptor for glial cell line-derived neurotrophic factor (GDNF) and other ligands of the GDNF family that have potent effects on brain dopaminergic neurons. The Met918Thr mutation leads to constitutive activity of Ret receptor tyrosine kinase, causing the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). We used knock-in MEN2B mice with the Ret-MEN2B mutation to study the effects of constitutive Ret activity on the brain dopaminergic system and found robustly increased concentrations of dopamine (DA) and its metabolites in the striatum, cortex, and hypothalamus. The concentrations of brain serotonin were not affected and those of noradrenaline were slightly increased only in the lower brainstem. Tyrosine hydroxylase (TH) protein levels were increased in the striatum and substantia nigra/ventral tegmental area (SN/VTA), and TH mRNA levels were increased in SN/VTA of MEN2B mice, suggesting that constitutive Ret activity increases DA levels by increasing its synthesis. Also, the striatal DA transporter protein levels in the MEN2B mice were increased, which agrees with increased sensitivity of these mice to the stimulatory effects of cocaine. In the SN pars compacta of homozygous MEN2B mice, we found a 26{\%} increase in the number of TH-positive cells, but no differences were found in the VTA. Thus, we show here that the constitutive Ret activity in mice is sufficient to increase the number of dopaminergic neurons and leads to profound elevation of brain DA concentration. These data clearly suggest that Ret activity per se can have a direct biological function that actively changes and shapes the brain dopaminergic system.",
    author = "Jelena Mijatovic and Mikko Airavaara and Anu Planken and Petri Auvinen and Atso Raasmaja and Petteri Piepponen and Frank Costantini and Liisa Ahtee and Mart Saarma",
    year = "2007",
    doi = "10.1523/JNEUROSCI.5647-06.2007",
    language = "English",
    volume = "27",
    pages = "4799--4809",
    journal = "Journal of Neuroscience",
    issn = "0270-6474",
    publisher = "Society of Neuroscience",
    number = "18",

    }

    TY - JOUR

    T1 - Constitutive ret activity in knock-in multiple endocrine neoplasia type B mice induces profound elevation of brain dopamine concentration via enhanced synthesis and increases the number of TH-positive cells in the substantia nigra

    AU - Mijatovic, Jelena

    AU - Airavaara, Mikko

    AU - Planken, Anu

    AU - Auvinen, Petri

    AU - Raasmaja, Atso

    AU - Piepponen, Petteri

    AU - Costantini, Frank

    AU - Ahtee, Liisa

    AU - Saarma, Mart

    PY - 2007

    Y1 - 2007

    N2 - Ret is the common signaling receptor for glial cell line-derived neurotrophic factor (GDNF) and other ligands of the GDNF family that have potent effects on brain dopaminergic neurons. The Met918Thr mutation leads to constitutive activity of Ret receptor tyrosine kinase, causing the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). We used knock-in MEN2B mice with the Ret-MEN2B mutation to study the effects of constitutive Ret activity on the brain dopaminergic system and found robustly increased concentrations of dopamine (DA) and its metabolites in the striatum, cortex, and hypothalamus. The concentrations of brain serotonin were not affected and those of noradrenaline were slightly increased only in the lower brainstem. Tyrosine hydroxylase (TH) protein levels were increased in the striatum and substantia nigra/ventral tegmental area (SN/VTA), and TH mRNA levels were increased in SN/VTA of MEN2B mice, suggesting that constitutive Ret activity increases DA levels by increasing its synthesis. Also, the striatal DA transporter protein levels in the MEN2B mice were increased, which agrees with increased sensitivity of these mice to the stimulatory effects of cocaine. In the SN pars compacta of homozygous MEN2B mice, we found a 26% increase in the number of TH-positive cells, but no differences were found in the VTA. Thus, we show here that the constitutive Ret activity in mice is sufficient to increase the number of dopaminergic neurons and leads to profound elevation of brain DA concentration. These data clearly suggest that Ret activity per se can have a direct biological function that actively changes and shapes the brain dopaminergic system.

    AB - Ret is the common signaling receptor for glial cell line-derived neurotrophic factor (GDNF) and other ligands of the GDNF family that have potent effects on brain dopaminergic neurons. The Met918Thr mutation leads to constitutive activity of Ret receptor tyrosine kinase, causing the cancer syndrome called multiple endocrine neoplasia type B (MEN2B). We used knock-in MEN2B mice with the Ret-MEN2B mutation to study the effects of constitutive Ret activity on the brain dopaminergic system and found robustly increased concentrations of dopamine (DA) and its metabolites in the striatum, cortex, and hypothalamus. The concentrations of brain serotonin were not affected and those of noradrenaline were slightly increased only in the lower brainstem. Tyrosine hydroxylase (TH) protein levels were increased in the striatum and substantia nigra/ventral tegmental area (SN/VTA), and TH mRNA levels were increased in SN/VTA of MEN2B mice, suggesting that constitutive Ret activity increases DA levels by increasing its synthesis. Also, the striatal DA transporter protein levels in the MEN2B mice were increased, which agrees with increased sensitivity of these mice to the stimulatory effects of cocaine. In the SN pars compacta of homozygous MEN2B mice, we found a 26% increase in the number of TH-positive cells, but no differences were found in the VTA. Thus, we show here that the constitutive Ret activity in mice is sufficient to increase the number of dopaminergic neurons and leads to profound elevation of brain DA concentration. These data clearly suggest that Ret activity per se can have a direct biological function that actively changes and shapes the brain dopaminergic system.

    U2 - 10.1523/JNEUROSCI.5647-06.2007

    DO - 10.1523/JNEUROSCI.5647-06.2007

    M3 - Article

    VL - 27

    SP - 4799

    EP - 4809

    JO - Journal of Neuroscience

    JF - Journal of Neuroscience

    SN - 0270-6474

    IS - 18

    ER -